The Critical Role of Aberrant DNA Methylation and Long Non-Coding RNAs in Melanoma Pathogenesis

Abstract

Background and Aims. Malignant melanoma is the most lethal form of skin cancer, characterized by a high mortality rate and an inherent ability to metastasize to distant organs and tissues. Although current therapeutic approaches yield favorable clinical outcomes, the involvement of an aberrant epigenetic landscape—such as altered DNA methylation patterns and/or dysregulated non-coding RNA expression—in addition to the genetic background, has been linked to melanoma initiation, progression, and resistance to anticancer therapy. The aim of this review is to summarize emerging trends and unresolved issues regarding aberrant DNA methylation and non-coding RNA dysregulation, including long non-coding RNAs (lncRNAs), in melanoma. We have comprehensively analyzed recent data to provide a foundation for understanding the current state of research in this area. For clarity, the review highlights several key factors involved in DNA methylation changes and alterations in lncRNA expression in melanoma. We hope that this work will contribute to accelerating the translation of DNA methylation and lncRNA research into diagnostic, prognostic, and therapeutic applications for melanoma patients. Methods. An analysis of international research data on the role of epigenetic mechanisms in melanoma development was conducted. Based on the reviewed materials, the article is divided into three sections, each addressing a distinct mechanism or group of processes underlying the malignant transformation of skin cells and the potential prerequisites for such transformation. Only studies providing convincing evidence of pathway involvement in melanoma pathogenesis were included. Results. Disruption of systemic regulatory processes that maintain the balance of interacting molecular cascades plays a pivotal role in malignant transformation. According to the summarized findings, the processes of DNA methylation and demethylation, along with their regulatory factors—particularly long non-coding RNAs and their associated genes—represent key elements capable of inducing irreversible disturbances in the homeostasis of epithelial skin cells, ultimately leading to melanoma formation. Conclusion. Identifying and cataloguing aberrant events—such as alterations in DNA methylation status, level, and profile, and/or changes in lncRNA expression—that contribute to melanoma development represent a critical first step toward understanding the epigenetic landscape of this malignancy. It is essential to clearly determine whether aberrant gene methylation and/or abnormal expression of their regulators act as driver or passenger processes in melanoma progression. This distinction is crucial not only for patient screening but also for the development of individualized therapeutic strategies. Therefore, targeted searches for potential biomarkers of malignant transformation are necessary to improve the effectiveness of treatment approaches for various melanoma cases.